The present invention relates to a novel compound represented by the following formula (1) which has a pyrrole structure and shows an inhibitory activity against farnesyl transferase: 
in which
A represents hydrogen, lower alkyl, or a structure selected from the following group: 
wherein
m1, m2, m and n independently of one another denote an integer of 0 to 5,
Y represents O, S, Sxe2x95x90O or SO2,
R1 represents hydrogen, or represents optionally saturated 3- to 6-membered heterocycle or bicyclo 9- to 10-membered aromatic heterocycle, each of which has one or more hetero atoms selected from a group consisting of nitrogen, sulfur and oxygen, or represents a structure selected from the following group: 
wherein,
X represents hydrogen, halogen, lower alkyl, lower alkoxy, nitro, cyano, hydroxy or phenoxy,
R2 represents optionally saturated 3- to 9-membered heterocycle or bicyclo 9- to 10-membered aromatic heterocycle, each of which has one or more hetero atoms selected from a group consisting of nitrogen, sulfur and oxygen, or represents a structure selected from the following group: 
wherein,
p denotes an integer of 1 to 3, Y is defined as previously described, R11 and R12 independently of one another represent lower alkyl optionally substituted by phenyl or naphthyl, or represent C3-C7-cycloalkyl, phenyl or naphthyl,
R3 represents lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl or lower alkylsulfonyl, each of which is optionally substituted by phenyl or naphthyl, or represents sulfonyl substituted by phenyl or naphthyl,
R4 and R8 independently of one another represent hydrogen, lower alkyl, lower alkoxy or halogen,
R5 and R7 independently of one another represent hydrogen, lower alkyl, lower alkoxy, halogen or hydroxy,
R6 represents hydrogen, lower alkyl, lower alkoxy, hydroxy, di(lower alkyl)amine, C3-C6-cycloalkyl, C3-C6-cycloalkyl-lower alkyl, halogen, phenyl or phenoxy,
R9 represents hydrogen or lower alkyl,
R10 represents aralkyl optionally substituted by lower alkyl or halogen,
B represents hydrogen, lower alkyl, lower alkylthio or amino,
D represents hydrogen, lower alkyl, halogen, lower alkylthio, nitro or amino,
E represents phenyl, or naphthyl optionally substituted by halogen,
G represents nitro or amino, or represents a structure of 
wherein
L represents a structure selected from the following group: 
wherein
R13 and R14 independently of one another represent hydrogen, hydroxy, lower alkyl or lower alkoxy,
Y is defined as previously described,
J represents hydrogen, lower alkyl, lower alkylthio or phenyl,
provided that A does not represent hydrogen, lower alkyl or any one structure selected from the following group: 
wherein m and R3 to R9 are defined as previously described, mxe2x80x2 denotes an integer of 1 to 5, when B, J and D represent hydrogen at the same time and G does not represent nitro or amino, or pharmaceutically acceptable salts or isomers thereof.
The present invention also includes processes for the preparation of said compound of formula (1), and compositions useful for treating or preventing cancer, restenosis (Erick E. Brooks, et. al. The Journal of Biological Chemistry, 272 (14), 29207-29211, 1997), atherosclerosis (Russell Ross, Nature, 362, 801-809, 1993; Joseph L. Goldstein, et. al., Nature, 343, 425-430, 1990) or infections from viruses (James C. Otto, et. al., The Journal of Biological Chemistry, 272(9), 4569-4572, 1996), which comprise as an active ingredient the compound of formula (1) together with the pharmaceutically acceptable carrier. Therefore, those processes and compositions are subject matters of the present invention.
Ras is a 21 kDa protein which plays an important role in the events associated with cell growth and differentiation. It combines with guanine nucleotide, whereby catalyzes the hydrolysis reaction from guanosine triphosphate (GTP) to guanosine diphosphate (GDP). Further, this protein has been reported to act as a molecular switch regulating the specific GTPase cycle inside the cell (see: Bourne, H. R., Sanders, D. A., McCormick, F. Nature 1991, 349, 117).
The mammalian Ras protein is coded by three (3) types of ras gene and classified into four (4) types; i.e., K-Ras-4B consisting of 188 amino acid residues and H-Ras, K-Ras-4A and N-Ras consisting of 189 residues, respectively. Amino acids 12, 13 and 61 of Ras, positioned in the neighborhood of phosphoryl group of GTP, regulate the activity of GTPase by having a large effect on spacial position of a water molecule which participates in the GTP hydrolysis. In human cancers, mutations are observed at the above amino acid positions. Since Ras mutations inhibit its ability to regulate GTPase activity, GTP-binding state of Ras is maintained, and thus, growth signal is transduced abnormally to cause cancer. In particular, ras oncogene is related to pancreatic cancer, urinary bladder carcinoma, lung cancer and skin cancer, etc. (see: Bos, J. L., Cancer Res., 1989, 49, 4682).
To be in its biologically activated state, Ras must be attached to cell membrane and for this reason, modification or carboxyl terminus of the protein is required after the transportation of protein. The modification process comprises the steps of farnesylation of Ras by Ras farnesyl transferase, displacement of AAX peptide consisting of 3 amino acids at the C-terminus of Ras by peptide cleavage enzyme, methyl esterification of Ras by methyl transferase and palmitoylation of Ras by palmitoyl transferase. Among the above-described steps of modifying carboxyl terminus of Ras, the farnesylation step is proceeded by farnesyl transferase (FTase), and substrate for the transferase is CA1A2X peptide consisting of 4 amino acids at the C-terminus or Ras, where A1 and A2 are aliphatic amino acids having no charge and X is methionine, alanine or serine, etc. The farnesylation occurs at cysteine, and sulfur ether bond is formed. While, in H-Ras and N-Ras, palmitoylation occurs at another cysteine proximate to the C-terminus. The above-described farnesylation results in the enhancement of hydrophobicity of Ras, and hence its affinity for cell membrane increases. The farnesylated Ras is subjected to the cleavage of AAX peptide from the C-terminus thereof by the cleavage enzyme and methyl-esterified so that it can attach to the lipid layer of cell membrane or other receptors more easily. K-Ras-4B, differently from H-Ras or N-Ras, has a multiple lysine-arranged-region named polybasic domain, instead of having cysteine required for palmitoylation. It has been known that the polybasic domain facilitates Ras to bind to anionic lipid of cell membrane. All the above-described steps attribute to enhancing the attachment of Ras to cell membrane under the optimal condition, but only the farnesylation step is essentially required to express the biological activity of Ras. That is, if farnesylation step is inhibited, the resulting mutant Ras is prevented from being attached to cell membrane. Hence, inhibitors of farnesylation have been subjects of many studies (see: J. E. Buses et al., Chemistry and Biology, 1995, 2, 787).
As results of the studies, when farnesyl transferase is inhibited in a cell transformed by Ras, it is observed that the conditions of abnormal cells caused by mutant Ras are improved while growth of cells is inhibited.
Several inhibitors of farnesyl transferase are found to selectively inhibit intracellular prenyl group reaction of oncogenic Ras (see: Kohl, N. E. et al., Proc. Natl. Acad. Sci. USA, 91, 9141(1994); Kohl, N. E. et al., Nature Medicine, 1, 792(1995)). The inhibitors of farnesyl transferase being studied recently include peptide variants having cysteine thiol group imitating CAAX and improved inhibitors (see: U.S. Pat. No. 5,141,851; Kohl, N. E. et al., Science, 260, 1934(1993); Graham et al., PCT/US95/12224), peptides modified by phenyl group (see: Sebti, S. M., J. Biol. Chem., 270, 26802, 1995), variants using benzodiazepin, a frame structure of positive psycopharmaceuticals, as turn-imitating structure of peptide (see: James, G. L. et al., Science, 260, 1937, 1993) and inhibitors having tricyclic organic compound frame deviating its peptide structure (see: Bishop, W. R. et al., J. Biol. Chem., 270, 30611, 1995). In addition, a new type of inhibitor wherein (+) charge in the transition state is linked with the prenyl group has been reported. It was designed upon the notice that since the reaction mechanism in the transfer of prenyl group by farnesyl transferase is a type of electrophilic displacement, this reaction requires (+) charge in transition state (see: Poulter, C. D. et al., J. Am. Chem. Soc., 118, 8761, 1996).
However, the activation of K-Ras has been found in most human cancers, and most of the prenyl transferase inhibitors developed hitherto are found to activate K-Ras. The existing inhibitors inhibit the growth of cells transformed with K-Ras less effectively than that with H-Ras or N-Ras. Therefore, new inhibitor having the capability of effectively inhibiting K-Ras activity is required.
Thus, the present inventors established a new evaluation system by which the inhibitory activity against enzyme action for K-Ras substrate and inhibitory activity against intracellular K-Ras prenylation can be determined. Then, we synthesized novel compounds inhibiting the farnesylation of H-Ras, N-Ras as well as K-Ras and screened them using said new system. As a result, we have found that the compound of formula (1) as defined above can be used as an effective anti-cancer agent, etc., and then completed the present invention. Particularly, the compound according to the present invention has a characteristic structure different from those of the existing inhibitors against farnesyl transferase and does not include any thiol group.
Therefore, the object of the present invention is to provide the compound of formula (1) having a superior anti-cancer effect and process for preparation thereof.
It is another object of the present invention to provide compositions for treating cancer, restenosis, atherosclerosis and viral infections, respectively, each of which comprises as an active ingredient the compound of formula (1) together with the pharmaceutically acceptable carrier.
The present invention relates to a compound of the following formula (1) which has a pyrrole structure and shows an inhibitory activity against farnesyl transferase: 
in which
A represents hydrogen, lower alkyl, or a structure selected from the following group: 
wherein
m1, m2, m and n independently of one another denote an integer of 0 to 5,
Y represents O, S, Sxe2x95x90O or SO2,
R1 represents hydrogen, or represents optionally saturated 3- to 6-membered heterocycle or bicyclo 9- to 10-membered aromatic heterocycle, each of which has one or more hetero atoms selected from a group consisting of nitrogen, sulfur and oxygen, or represents a structure selected from the following group: 
wherein,
X represents hydrogen, halogen, lower alkyl, lower alkoxy, nitro, cyano, hydroxy or phenoxy,
R2 represents optionally saturated 3- to 9-membered heterocycle or bicyclo 9- to 10-membered aromatic heterocycle, each of which has one or more hetero atoms selected from a group consisting of nitrogen, sulfur and oxygen, or represents a structure selected from the following group: 
wherein,
p denotes an integer of 1 to 3, Y is defined as previously described, R11 and R12 independently of one another represent lower alkyl optionally substituted by phenyl or naphthyl, or represent C3-C7-cycloalkyl, phenyl or naphthyl,
R3 represents lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl or lower alkylsulfonyl, each of which is optionally substituted by phenyl or naphthyl, or represents sulfonyl substituted by phenyl or naphthyl,
R4 and R8 independently of one another represent hydrogen, lower alkyl, lower alkoxy or halogen,
R5 and R7 independently of one another represent hydrogen, lower alkyl, lower alkoxy, halogen or hydroxy,
R6 represents hydrogen, lower alkyl, lower alkoxy, hydroxy, di(lower alkyl)amine, C3-C6-cycloalkyl, C3-C6-cycloalkyl-lower alkyl, halogen, phenyl or phenoxy,
R9 represents hydrogen or lower alkyl,
R10 represents aralkyl optionally substituted by lower alkyl or halogen,
B represents hydrogen, lower alkyl, lower alkylthio or amino,
D represents hydrogen, lower alkyl, halogen, lower alkylthio, nitro or amino,
E represents phenyl, or naphthyl optionally substituted by halogen,
G represents nitro or amino, or represents a structure of 
wherein
L represents a structure selected from the following group: 
wherein
R13 and R14 independently of one another represent hydrogen, hydroxy, lower alkyl or lower alkoxy,
Y is defined as previously described,
J represents hydrogen, lower alkyl, lower alkylthio or phenyl,
provided that A does not represent hydrogen, lower alkyl or any one structure selected from the following group: 
wherein m and R3 to R9 are defined as previously described, mxe2x80x2 denotes an integer of 1 to 5, when B, J and D represent hydrogen at the same time and G does not represent nitro or amino, or pharmaceutically acceptable salts or isomers thereof.
Among the compound of formula (1) having a superior inhibitory activity against farnesyl transferase, the preferred compounds include those wherein
A represents lower alkyl or a structure selected from the following group: 
wherein
m1, m2, m and n independently of one another denote an integer of 0 to 3,
Y represents O or S,
R1 represents hydrogen, or represents a structure selected from the following group: 
wherein,
X represents hydrogen, halogen, lower alkyl, lower alkoxy, nitro, cyano, hydroxy or phenoxy,
R2 represents optionally saturated 3- to 9-membered heterocycle having one or more hetero atoms selected from a group consisting of nitrogen, sulfur and oxygen, or represents a structure of 
wherein,
p denotes an integer of 1 or 2 and Y represents O,
R3 represents lower alkyl optionally substituted by phenyl or naphthyl,
R4 and R8 independently of one another represent hydrogen or lower alkoxy,
R5 and R7 independently of one another represent hydrogen, lower alkoxy or halogen,
R6 represents hydrogen, lower alkyl, lower alkoxy or halogen,
R9 represents hydrogen,
R10 represents aralkyl optionally substituted by lower alkyl or halogen,
B represents hydrogen, lower alkyl, lower alkylthio or amino,
D represents hydrogen, lower alkyl, halogen, nitro or amino,
E represents naphthyl optionally substituted by halogen,
G represents nitro or amino, or represents a structure of 
wherein
L represents a structure selected from the following group: 
wherein
R13 and R14 independently of one another represent lower alkyl or lower alkoxy,
Y represents O or S,
J represents hydrogen, lower alkyl or lower alkylthio.
Typical examples of the compound of formula (1) according to the present invention are exemplified in the following (the numbers in the parenthesis represent the number of examples) with the structures of Table 1:
1-[1-(3-benzyloxypropyl)-1H-imidazol-5-yl]methyl-3-[N-(2-methoxy ethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(1);
1-[1-(3-benzyloxypropyl)-1H-imidazol-5-yl]methyl-3-(morpholin-4-yl) carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(2);
1-[1-(3-benzyloxypropyl)-1H-imidazol-5-yl]methyl-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(3);
3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1-[1-(3-phenoxypropyl)-1H-imidazol-5-yl]methyl-1H-pyrrole(4);
3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1-[1-(3-thiophenoxypropyl)-1H-imidazol-5-yl]methyl-1H-pyrrole(5);
3-(morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1-[1-(3-phenoxypropyl)-1H-imidazol-5-yl]methyl-1H-pyrrole(6);
3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1-[1-(3-phenoxypropyl)-1H-imidazol-5-yl]methyl-1H-pyrrole(7);
3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1-[1-(3-thioethoxypropyl)-1H-imidazol-5-yl]methyl-1H-pyrrole(8);
3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-1-{1-[3-(morpholin-4-yl) propyl]-1H-imidazol-5-yl}methyl-4-(naphthalen-1-yl)-1H-pyrrole(9);
3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1-{1-[2-(thiophen-2-yl)ethyl]-1H-imidazol-5-yl}methyl-1H-pyrrole(10);
3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1-{1-[2-(thiophen-2-yl)ethyl]-1H-imidazol-5-yl}methyl-1H-pyrrole(11);
1-[1-(furan-2-yl)methyl-1H-imidazol-5-yl]methyl-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(12);
1-[1-(1-benzylpiperidin-4-yl)-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(13);
1-[1-(1-benzylpiperidin-4-yl)-1H-imidazol-5-yl]methyl-3-(morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(14);
1-[2-methyl-1-(3,4-methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(15);
1-[4-methyl-1-(3,4-methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(16);
1-[2-amino-1-(3,4-methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(17);
1-[1-(3,4-methylenedioxybenzyl)-2-methylthio-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(18);
1-[1-(3,4-methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-2-methylthio-4-(naphthalen-1-yl)-1H-pyrrole(19);
1-[4-iodo-1-(3,4-methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(20);
1-[1-(3,4-methylenedioxybenzyl)-4-nitro-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(21);
1-[4-amino-1-(3,4-methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(22);
3-(4-methoxypiperazin-1-yl)carbonyl-1-[4-methyl-1-(3,4-methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-1H-pyrrole(23);
2-methyl-1-[2-(3,4-methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(24);
2-ethylthio-1-[1-(3,4-methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(25);
1-[1-(2-methoxyphenethyl)-2-methyl-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(26);
1-[1-(3-ethoxypropyl)-2-methyl-1H-imidazol-5-ylmethyl]-3-(4-methyl piperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(27);
1-[1-(3-ethoxypropyl)-4-methyl-1H-imidazol-5-ylmethyl]-3-(4-methyl piperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(28);
1-[1-(3-benzyloxypropyl)-4-methyl-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(29);
1-[1-(3-benzyloxypropyl)-4-methyl-1H-imidazol-5-ylmethyl]-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(30);
1-{1-[3-(2-chlorobenzyloxy)propyl]-4-methyl-1H-imidazol-5-ylmethyl}-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(31);
1-{1-[3-(2-chlorobenzyloxy)propyl]-4-methyl-1H-imidazol-5-ylmethyl}-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole (32);
1-[1-(3-benzyloxypropyl)-2-methyl-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(33);
1-[1-(3-benzyloxypropyl)-2-methyl-1H-imidazol-5-ylmethyl]-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(34);
1-[1-(phenethyl)-2-methyl-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(35);
1-[1-(3,4-methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole(36);
1-[1-(4-chlorobenzyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole(37);
1-[1-(4-bromobenzyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole(38);
1-[1-(phenethyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole(39);
1-[1-(4-methylphenethyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole(40);
1-[1-(4-chlorophenethyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole(41);
1-[1-(4-fluorophenethyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole(42);
1-[1-(3-bromophenethyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole(43);
1-[1-(4-methoxyphenethyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole(44);
1-[1-(3-methoxyphenethyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole(45);
1-[1-(naphthalen-1-ylethyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole(46);
1-[1-(3-ethoxypropyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole(47);
1-[1-(methyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole(48);
1-[1-(naphthalen-2-ylmethyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole(49);
3-amino-1-[1-(4-chlorobenzyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-1H-pyrrole(50);
4-(3-bromonaphthalen-1-yl)-1-[4-methyl-1-(3,4-methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-1H-pyrrole(51);
4-(3-chloronaphthalen-1-yl)-1-[4-methyl-1-(3,4-methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-1H-pyrrole(52);
4-(3-bromonaphthalen-1-yl)-1-[4-methyl-1-(naphthalen-2-yl)methyl-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-1H-pyrrole(53);
4-(3-chloronaphthalen-1-yl)-1-[4-methyl-1-(naphthalen-2-yl)methyl-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-1H-pyrrole(54); and
1-[4-methyl-1-(naphthalen-2-yl)methyl-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(55).
The compound of formula (1) as explained above can be prepared characterized by
(a) coupling a compound represented by the following formula (2) with a compound represented by the following formula (3) to give the compound of formula (1);
(b) coupling a compound represented by the following formula (4a) with a compound represented by the following formula (5) to give a compound represented by the following formula (1a);
(c) coupling a compound represented by the following formula (4b) with a compound represented by the following formula (6) to give a compound represented by the following formula (1b);
(d) coupling a compound represented by the following formula (7) with a compound represented by the following formula (8) to give a compound represented by the following formula (1c);
or further introducing substituents in the presence of a base, or reducing. Therefore, these processes for preparing the compound of formula (1) are also subject matters to be provided by the present invention. 
in which
A, B, D, J, E, G, m1, m2, n, Y, R1, R2 and L are defined as previously described.
If desired, the coupling reactions in said process variants (a) to (d) for preparing the compound of formula (1) according to the present invention may be carried out in a solvent in the presence of a base. Any solvent which does not adversely affect the reaction may be used, but one or more selected from a group consisting of dimethylformamide, dichloromethane, tetrahydrofuran, chloroform and dimethylacetamide are preferable. As the base, one or more selected from a group consisting of sodium hydride, potassium t-butoxide, sodium bis(trimethylsilyl)amide, sodium amide and potassium bis(trimethylsilyl)amide can be mentioned.
The process variant (d) wherein carboxylic acid and hydroxy group are directly reacted with each other without using a reactive leaving group in the coupling reaction, may be preferably carried out particularly in the presence of a coupling agent. For example, coupling agents such as dicyclohexylcarbodiimide(DCC), 3-ethyl-3xe2x80x2-(dimethylamino)-propylcarbodiimide(EDC), bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride (BOP-C1), diphenylphosphorylazide(DPPA), isobutyl chloroformate, O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate(HATU), etc. may be used together with 1-hydroxy benzotriazole (HOBT).
While the compounds used as starting materials in said processes for preparing the compound of formula (1) may be prepared according to the process depicted in the following Reaction Schemes 1 to 9.
First, as depicted in the following Reaction Scheme 1, the compound of formula (2) wherein 2-position of the imidazole ring is substituted by methyl group may be prepared by reacting an amine with dihydroxyacetone to give a thiolimidazole derivative, then by desulfurizing, methylating and halogenating (see: J. Med. Chem., 33, 1312-1329, 1990). Further, the compound of formula (2) wherein 4-position of the imidazole ring is substituted may be prepared by the processes described in Reaction Scheme 2or 3. 
In the above Reaction Schemes 1, 2, 3
A is defined as previously described,
TBDMS means t-butyldimethylsilyl,
TBAF means tetrabutylammoniumfluoride, and
they have the same meaning hereinafter.
The compound of formula (3) wherein J is hydrogen and G is the structure of 
may be prepared from an aldehyde derivative of a formula E-CHO according to the process depicted in the following Reaction Scheme 4. The final step for giving the compound of formula (3a) from pyrrole carboxylic acid may be preferably carried out in the presence of the coupling agents as forementioned for process variants (a) to (d) (The preparation example for the starting compound of E-CHO where E is naphthyl substituted by halogen is described in Reaction Scheme 5). Further the compound of formula (3) wherein J is lower alkylthio or lower alkyl may be prepared by the processes described in the following Reaction Scheme 6 or 7, and the compound of same formula wherein G is nitro may be synthesized by the process described in the following Reaction Scheme 8. 
In the above Reaction Schemes 4, 5, 6, 7, 8
E and L are defined as previously described,
Hal means halogen,
CAN means cerium ammonium nitrate,
R15 and R16 represent lower alkyl,
DBU means 1,8-diazabicyclo[5,4,0]undec-7-ene,
TosMIC means tosylmethylisocyanide,
EDC means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,
HOBT means 1-hydroxybenzotriazole hydrate, and
TEA means triethylamine.
While, The compounds of formulae (4a) and (4b) may be prepared from aminoalcohol derivatives according to the following Reaction Scheme 9. 
In the above Reaction Scheme 9
B, D, E, G and J are defined as previously described,
q represents m1+2 or n.
That is, the aminoalcohol derivative is reacted with phthalic acid anhydride in the presence of toluene to protect the amine moiety, and then the hydroxy group is reacted with benzylbromide in the presence of sodium hydride to be protected. The compound wherein both amino group and hydroxy group are protected is reacted with hydrazine to remove the phthalic protecting group, and thus, to give an amine compound wherein only the hydroxy group is protected by benzyl group. This amine compound is reacted according to the same procedure as Reaction Scheme 1, 2 or 3, and then the resulting compound is reacted with the compound of formula (3) and deprotected to give a primary alcohol compound. The primary alcohol is reacted with methanesulfonylchloride to give the desired compound of formula (4a) or (4b).
The reaction conditions including the amount of reactants, reaction temperature, reaction time, etc. in the processes according to the present invention can easily be determined by a person skilled in the art depending on the specific reactants.
In addition, the compound of formula (1) produced in the above processes in the form of a free base can easily be converted to a salt form according to the conventional methods known per se in this art.
After the reaction is completed, the resulting product may be further separated and purified by usual work-up processes, such as for example, chromatography, recrystallization, etc.
The present invention particularly the processes as described above, will be more specifically explained by the following Preparations and Examples. However, the processes for preparing the compound according to the present invention are not restricted to those which are explained in the present specification. That is, the present invented compound may be easily prepared by optionally combining the processes disclosed in the present specification or known in the prior references, and such a combination is a common knowledge to those skilled in the art to which the present invention pertains.
The compound of the present invention shows an inhibitory activity against farnesyl transferase, and thus can be effectively used as an anti-cancer agent. Further, due to the inhibitory activity against farnesyl transferase, the compound of formula (1) can be used as an agent useful for restenosis, atherosclerosis or viral infections. Therefore, it is another object of the present invention to provide compositions for treating cancer, restenosis, atherosclerosis and viral infections, respectively, each of which comprises as an active ingredient the compound of formula (1), pharmaceutically acceptable salt or isomer thereof together with the pharmaceutically acceptable carrier.
When the active compound according to the present invention is used for clinical purpose, it is preferably administered in an amount ranging from 1 to 100 mg per kg of body weight a day. The total daily dosage may be administered in one time or over several times. However, the specific administration dosage for the patient can be varied with the specific compound used, body weight of the subject patient, sex, hygienic condition, diet, time or method of administration, excretion rate, mixing ratio of the agent, severity of the disease to be treated, etc.
The compound of the present invention may be administered in the form of injections or oral preparations. Injections, for example, sterilized aqueous or oily suspension for injection, can be prepared according to the known procedure using suitable dispersing agent, wetting agent, or suspending agent. Solvents which can be used for preparing injections include water, Ringer""s fluid and isotonic NaCl solution, and also sterilized fixing oil may be conveniently used as the solvent or suspending media. Any non-stimulative fixing oil including mono-, di-glyceride may be used for this purpose. Fatty acid such as oleic acid may also be used for injections.
As the solid preparation for oral administration, capsules, tablets, pills, powders and granules, etc., preferably capsules and tablets can be mentioned. It is also desirable for tablets and pills to be formulated into enteric-coated preparation. The solid preparations may be prepared by mixing the active compound of formula (1) according to the present invention with at least one carrier selected from a group consisting of inactive diluents such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate, disintegrating agent and binding agent.
The present invention will be more specifically explained in the following examples. The following Preparations are to explain the syntheses of intermediates used for preparing the final products, and the Examples are to explain the syntheses of final products through the reactions of the compounds obtained in the Preparations. However, it should be understood that these Preparations and Examples are intended to illustrate the present invention but not in any manner to limit the scope of the present invention.
1-1) Preparation of 3-(naphthalen-1-yl)-acrylic acid ethylester
22.4 g(0.10 mol) of triethylphosphonoacetate was dissolved in 500 ml of acetonitrile and 30.4 g(2mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5)(DBU) was slowly added thereto. 15.6 g(0.10 mol) of 1-naphthaldehyde dissolved in 20 ml of tetrahydrofuran was slowly added to the above reaction solution and the resulting mixture was stirred for 8 hours. The organic solvent was removed under reduced pressure, the residue thus obtained was dissolved in ethylacetate, washed twice with water, dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography(eluent: n-hexane/ethylacetate=95/5, v/v) to give 20.3 g(0.090 mol, Yield 90%) of the title compound.
1H NMR(CDCl3) xcex4 1.33 (t, 3H), 4.10 (q, 2H), 6.75 (q, 1H), 7.50 (m, 3H), 7.73 (d, 1H), 7.85 (m, 2H), 8.10 (d, 1H), 8.21 (d, 1H)
FAB 227 (M+H)
1-2) Preparation of ethyl 4-(naphthalen-1-yl)-1H-pyrrole-3-carboxylate
5 g(18.9 mmol) of the compound prepared in Preparation 1-1) and 3.68 g(18.9 mmol) of tosylmethylisocyanide were dissolved in 100 ml of tetrahydrofuran. 2.55 g(22.7 mmol) of potassium t-butoxide dissolved in 100 ml of tetrahydrofuran was slowly added thereto and the resulting mixture was refluxed for 30 minutes. 100 ml of water was added to the reaction solution to stop the reaction and the solvent was removed under reduced pressure. The residue was extracted with diethylether, washed with saturated sodium chloride solution and dried over magnesium sulfate. Then, the solvent was removed under reduced pressure and the residue was subjected to column chromatography(eluent: ethylacetate/n-hexane=⅓, v/v) to give 3.85 g(14.5 mmol, Yield 77%) of the title compound.
1H NMR(CDCl3) xcex4 1.27 (t, 3H), 4.07 (q, 2H), 6.76 (s, 1H), 7.28-7.47 (m, 5H), 7.59 (s, 1H), 7.82 (m, 2H), 9.99 (s, 1H)
FAB 266 (M+H)
1-3) Preparation of 4-(naphthalen-1-yl)-1H-pyrrole-3-carboxylic acid
To 2.64 g(10 mmol) of the compound prepared in Preparation 1-2) in 50 ml of 50% ethanol was added 2.24 g(40 mmol) of potassium hydroxide and the resulting mixture was refluxed for 7 hours. After cooling to room temperature, the pH of the solution was adjusted to 4-5 and the product was extracted with ethylacetate. The extract was dried over sodium sulfate and the solvent was removed under reduced pressure to give 1.62 g(8.1 mmol, Yield 81%) of the title compound. The product thus obtained was used in the next reaction without purification.
1H NMR(CDCl3) xcex4 6.60 (s, 1H), 7.32-7.49 (m, 5H), 7.54 (s, 1H), 7.84 (m, 2H), 9.92 (s, 1H)
FAB 238 (M+H)
To 234 mg(1 mmol) prepared in Preparation 1-3) in 2 ml of dimethylformamide was added 230 mg(1.2 mmol) of EDC, 101 mg(1 mmol) of triethylamine and 162 mg(1.7 mmol) of HOBT and the resulting mixture was stirred for 5 minutes at 0xc2x0 C. 124 mg(1 mmol) of N-(2-methoxyethyl)-N-methylamine hydrochloride was added thereto and the mixture was stirred for 5 hours at room temperature. The solvent was removed under reduced pressure and 10 ml of saturated aqueous potassium carbonate solution and 20 ml of ethylacetate were added. The organic layer washed with 10 ml of 1N aqueous hydrochloric acid solution, saturated sodium chloride solution and water, dried over sodium sulfate and then concentrated to give 246 mg(0.79 mmol, Yield 79%) of the title compound.
1H NMR(CDCl3) xcex4 2.46 (s, 2H), 2.80-3.40 (m, 8H), 3.40 (s, 1H), 6.80 (s, 1H), 7.00 (s, 1H), 7.42 (m, 4H), 7.73 (d, 1H), 7.81 (d, 1H), 8.17 (d, 1H), 10.66 (s, 1H)
FAB 309 (M+H)
234 mg(1 mmol) of the compound prepared in Preparation 1-3) was dissolved in 2 ml of dimethylformamide, 230 mg(1.2 mmol) of EDC and 162 mg(1.7 mmol) of HOBT were added and the resulting mixture was stirred for 5 minutes at 0xc2x0 C. 87 mg(1mmol) of morpholine was added thereto and the mixture was stirred for 5 hours at room temperature. The solvent was removed under reduced pressure and 10 ml of saturated aqueous potassium carbonate solution was added. The resulting mixture was extracted with ethylacetate, washed with 10 ml of 1N aqueous hydrochloric acid solution, washed with aqueous sodium chloride solution and water, dried over sodium sulfate and then concentrated to give 243 mg(0.8 mmol, Yield 80%) of the title compound.
1H NMR(CDCl3) xcex4 2.13-3.52 (br, 8H), 6.54 (s, 1H), 7.31-7.51 (m, 5H) 7.53 (s, 1H), 7.81 (m, 2H), 9.93 (s, 1H)
FAB 307 (M+H)
The compound prepared in Preparation 1-3) was reacted with 4-methylpiperazine according to the same procedure as Preparation 2 to give the title compound with a yield of 75%.
1H NMR(CDCl3) xcex4 1.15 (br, 2H), 1.87 (br, 2H), 1.92 (s, 3H), 2.96 (br, 2H), 3.41 (br, 2H), 6.83 (s, 1H), 7.09 (s, 1H), 7.36-7.42 (m, 4H), 7.73 (d, 1H), 7.75 (d, 1H), 8.10 (d, 1H), 10.52 (s, 1H)
FAB (M+H): 320
5-1) Preparation of 3-hydroxypropyl phthalimide
15.2 g(0.2 mol) of 3-amino-1-propanol and 29.6 g(0.2 mol) of phthalic anhydride was refluxed with 500 ml of toluene using Dean-Stark apparatus for 24 hours(see: Tetrahedron Letter, 34, 2947, 1993). After the reaction, the solvent was removed under reduced pressure, and the residue was dissolved in 300 ml of dichloromethane and washed with 100 ml of water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give 33.6 g(Yield 80%) of the title compound.
1H NMR (CDCl3) xcex4 1.57 (m, 2H), 3.17 (t, 2H), 3.42 (t, 2H), 7.68 (m, 5H)
FAB (M+H): 206
5-2) Preparation of 3-benzyloxypropyl amine
To 20.5 g(0.1 mol) of the compound prepared in Preparation 5-1) in 40 ml of dimethylformamide was added 4.4 g(0.11 mol) of sodium hydride(60%). 18.9 g(0.11 mol) of benzyl bromide was added and the resulting mixture was reacted for 12 hours. After removal of solvent the reaction, solvent was removed and the residue was dissolved in ethylacetate and the organic layer was washed with saturated sodium bicarbonate solution. After removal of solvent, 200 ml of ethanol and 12.5 g(0.25 mol) of hydrazine hydrate was added thereto, and the resulting mixture was refluxed for 3 hours. After the reaction, solvent was removed under reduced pressure. The residue was dissolved in 200 ml of dichloromethane and the organic layer was washed with saturated sodium bicarbonate solution. 200 ml of 1N aqueous hydrochloric acid solution was added and the organic layer was removed. To the aqueous layer was added 200 ml of dichloromethane, and the resulting solution was basified with 6N sodium hydroxide solution. The organic layer was separated and the solvent was removed under reduced pressure to give 8.3 g(Yield 50%) of the title compound.
1H NMR(CDCl3) xcex4 1.76(m, 2H), 2.30(br, 2H), 2.83 (t, 2H), 3.54(t, 2H), 4.49(s, 2H), 7.32(m, 5H)
FAB 166 (M+H)
The title compound was prepared by modifying the method described in the literature (see: J. Med. Chem., 33, 1312-1329, 1990) from dihydroxyacetone dimer and the compound prepared in Preparation 5-2). 4.95 g(30 mmol) of 3-benzyloxypropylamine, 2.97 g(16.5 mmol) of dihydroxyacetone dimer and 3.20 g(33 mmol) of potassium thiocyanide were added to 30 ml of isopropyl alcohol, 6 ml of acetic acid was added thereto, and the resulting mixture was reacted for 48 hours at room temperature. After the reaction, solvent was removed, 100 ml of ethylacetate was added, and the mixture was washed twice with 100 ml of water. The solvent was removed under reduced pressure, 30 ml of 30% nitric acid and 6.9 mg(0.1 mmol) of NaNO2 were added to the residue and stirred for 2 hours. To the reaction mixture was added 20 ml of ethylacetate. The organic layer was removed and 100 ml of ethylacetate was added to the aqueous layer. After the mixture was basified to pH12 using 6N aqueous sodium hydroxide solution, the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was concentrated. The concentrate was subjected to column chromatography(eluent: dichloromethane/methanol=93/7, v/v) to give 2.5 g(Yield 38%) of the title compound.
1H NMR(CDCl3) xcex4 2.05 (m, 2H), 3.41 (t, 2H), 4.10 (t, 2H), 4.45 (s, 2H), 4.55 (s+br, 3H), 6.84(s, 1H), 7.32(m, 5H), 7.42(s, 1H)
FAB 247 (M+H)
246 mg(1 mmol) of the compound prepared in Preparation 5-3) was dissolved in 3 ml of chloroform and 355 mg(3mmol) of thionyl chloride was added dropwise at 0xc2x0 C. After the resulting solution was stirred for 2 hours, the solvent was removed under reduced pressure and the remaining hydrochloride was removed to give the title compound with a yield of 95%. The product thus obtained was directly used in the next reaction without purification.
6-1) Preparation of 1-[2-(thiophen-2-yl)ethyl]-5-hydroxymethyl-1H-imidazole
The title compound was prepared by modifying the method described in the literature (see: J. Med. Chem., 33, 1312-1329, 1990) from dihydroxyacetone dimer and 2-(thiophen-2-yl)ethylamine. 1.37 g(10 mmol) of 2-(thiophen-2-yl)ethylamine, 1.08 g(6 mmol) of dihydroxyacetone dimer and 1.15 g(11 mmol) of potassium thiocyanide were added to 10 ml of isopropyl alcohol, 2 ml of acetic acid was added thereto, and the resulting mixture was stirred for 48 hours at room temperature. The reaction mixture was filtered and the resulting solid was washed twice with 5 ml of isopropyl alcohol and twice with 5 ml of water. The filtered solid was added to 20 ml of 10% aqueous nitric acid solution. To the reaction solution was added 10 mg of sodium nitrite at 0xc2x0 C. and the mixture was reacted for 1 hour at room temperature. The aqueous solution was washed with 10 ml of ethyl acetate, basified and recrystallized to give 1.16 g(Yield 49%) of the title compound.
1H NMR(CDCl3) xcex4 3.31 (t, 2H), 4.25 (t, 2H), 4.55 (s, 2H), 6.70 (d, 1H), 6.90 (m, 2H), 7.15(d, 1H), 7.25(s, 1H)
FAB 233 (M+H), C10H12N2OS(M)
6-2) Preparation of 1-[2-(thiophen-2-yl)ethyl]-5-chloromethyl-1H-imidazole hydrochloride
233 mg(1 mmol) of the compound prepared in Preparation 6-1) was dissolved in 3 ml of chloroform and 355 mg(3 mmol) of thionyl chloride was added dropwise at 0xc2x0 C. After the reaction mixture was stirred for 2 hours, the solvent was removed under reduced pressure, and the remaining hydrochloride was removed to give the title compound with a yield of 95%. The product thus obtained was directly used in the next reaction without purification.
7-1) Preparation of 1-(furan-2-yl)methyl-5-hydroxymethyl-1H-imidazole
0.97 g(10 mmol) of furfurylamine, 1.08 g(6 mmol) of dihydroxyacetone dimer and 1.15 g(11 mmol) of potassium thiocyanide were added to 10 ml of isopropyl alcohol, 2 ml of acetic acid was added thereto, and the resulting mixture was stirred for 48 hours at room temperature. The reaction mixture was filtered and the resulting solid was washed twice with 5 ml of isopropyl alcohol and twice with 5 ml of water. The filtered solid was added to 20 ml of 10% aqueous nitric acid solution. To the reaction solution was added 10 mg of sodium nitrite at 0xc2x0 C. and the mixture was reacted for 1 hour at room temperature. The aqueous solution was washed with 10 ml of ethylacetate, basified and recrystallized to give 1.07 g(Yield 60%) of the title compound.
1H NMR(CDCl3) xcex4 4.63 (s+br, 3H), 5.29 (s, 2H), 6.37 (d, 1H), 6.40 (m, 1H), 6.99 (s, 1H), 7.41(s, 1H), 7.65(s, 1H)
FAB 179 (M+H), C9H10N2O2(M)
7-2) Preparation of 1-(furan-2-yl)methyl-5-chloromethyl-1H-imidazole hydrochloride
205 mg(1 mmol) of the compound prepared in Preparation 7-1) was dissolved in 3 ml of chloroform and 355 mg(3 mmol) of thionyl chloride was added dropwise thereto at 30xc2x0 C. After the reaction mixture was stirred for 2 hours, the solvent was removed under reduced pressure, and the remaining hydrochloride was removed to give the title compound with a yield of 95%. The product thus obtained was directly used in the next reaction without purification.
8-1) Preparation of 1-(1-benzylpiperidin-4-yl)-5-hydroxymethyl-1H-imidazole
3.0 g(11.4 mmol) of 4-amino-1-benzylpiperidine hydrochloride, 1.00 g(5.7 mmol) of dihydroxyacetone dimer and 1.8 g(18.2 mmol) of potassium thiocyanide were added to 10 ml of isopropyl alcohol, 2 ml of acetic acid was added thereto, and the resulting mixture was stirred for 48 hours at room temperature. The reaction mixture was filtered and the resulting solid was washed twice with 5 ml of isopropyl alcohol and twice with 5 ml of water. The filtered solid was added to 20 ml of 10% aqueous nitric acid solution and cooled to 0xc2x0 C. To the reaction solution was added 10 mg of sodium nitrite and the mixture was reacted for 1 hour at room temperature. The aqueous solution was washed with 10 ml of ethylacetate, basified and recrystallized to give 1.2 g(Yield 38%) of the title compound.
1 H NMR(CDCl3) xcex4 1.94(m, 2H), 2.01(m, 2H), 2.12(m, 2H), 2.97(d, 2H), 3.52(s, 2H), 4.08(m, 1H), 4.54(s, 2H), 6.72(s, 1H), 7.20-7.31(m, 5H), 7.45(s, 1H)
FAB 272 (M+H), C16H21N3O(M)
8-2) Preparation of 1-(1-benzylpiperidin-4-yl)-5-chloromethyl-1H-imidazole hydrochloride
271 mg(1 mmol) of the compound prepared in Preparation 8-1) was dissolved in 3 ml of chloroform and 355 mg(3 mmol) of thionyl chloride was added dropwise thereto at 0xc2x0 C. After the reaction mixture was stirred for 2 hours, the solvent was removed under reduced pressure, and the remaining hydrochloride was removed to give the title compound with a yield of 95%. The product thus obtained was directly used in the next reaction without purification.